An unexpectedly large polyclonal repertoire of HPV-specific T cells is poised for action in patients with cervical cancer

Cancer Res. 2010 Apr 1;70(7):2707-17. doi: 10.1158/0008-5472.CAN-09-4299. Epub 2010 Mar 16.

Abstract

The diversity and extent of the local tumor-specific T-cell response in a given individual is largely unknown. We have performed an in-depth study of the local T-cell repertoire in a selected group of patients with cervical cancer, by systematic analyses of the proportion, breadth, and polarization of human papillomavirus (HPV) E6/E7-specific T cells within the total population of tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC). Isolated T cells were stimulated with sets of overlapping E6 and E7 peptides and analyzed by multiparameter flow cytometry with respect to activation, cytokine production, and T-cell receptor Vbeta usage. HPV-specific CD4+ and CD8+ T-cell responses were detected in TIL and TDLNC and their relative contribution varied between <1% and 66% of all T cells. In general, these HPV-specific responses were surprisingly broad, aimed at multiple E6 and E7 epitopes and involved multiple dominant and subdominant T-cell receptor Vbetas per single peptide-epitope. In most patients, only few IFNgamma-producing T cells were found and the amount of IFNgamma produced was low, suggesting that these are poised T cells, rendered functionally inactive within the tumor environment. Importantly, stimulation of the TIL and TDLNC with cognate antigen in the presence of commonly used Toll-like receptor ligands significantly enhanced the effector T-cell function. In conclusion, our study suggests that within a given patient with HPV-specific immunity many different tumor-specific CD4+ and CD8+ T cells are locally present and poised for action. This vast existing local T-cell population is awaiting proper stimulation and can be exploited for the immunotherapy of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines / immunology
  • DNA-Binding Proteins / immunology
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Human papillomavirus 16 / immunology*
  • Human papillomavirus 18 / immunology*
  • Humans
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Oncogene Proteins, Viral / immunology
  • Papillomavirus E7 Proteins / immunology
  • Papillomavirus Infections / immunology*
  • Papillomavirus Infections / virology*
  • Repressor Proteins / immunology
  • T-Lymphocytes / immunology*
  • Uterine Cervical Neoplasms / immunology*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology*

Substances

  • Cytokines
  • DNA-Binding Proteins
  • E6 protein, Human papillomavirus type 16
  • E6 protein, Human papillomavirus type 18
  • E7 protein, Human papillomavirus type 18
  • Epitopes, T-Lymphocyte
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Repressor Proteins
  • oncogene protein E7, Human papillomavirus type 16